Tumorangiogenese: Neue Ansätze zur Krebstherapie

Abstract

Tumor Angiogenesis: New Approaches to Cancer Therapy Growth and metastasis of solid tumors depend on the formation of new blood vessels which originate from the existing vascular system. These blood vessels grow into the tumor and thus provide the necessary nutrients and growth factors for tumor progression. At the same time, the newly formed blood vessels allow tumor cells to disseminate and form metastases in distant organs. Normally, vascular homeostasis is regulated by a balance of angiogenic and antiangiogenic mechanisms. Tumor-induced angiogenesis is mainly sustained by the production and secretion of angiogenic factors originating from tumor and stroma cells. The most prominent angiogenic factor is the vascular endothelial growth factor (VEGF). Recently, additional angiogenic factors and their respective receptors have been identified and related to tumor angiogenesis. Among these, the angiopoietins and their receptor TIE-2 have been investigated to some detail. Angiopoietin-1 which binds to and activates TIE-2 is obviously responsible for the stabilization of vessels under homeostatic conditions. Angiopoietin-2 binds to the same receptor as angiopoietin-1 but is antagonistic with respect to angiopoietin-1. It destabilizes blood vessels and, under appropriate conditions, induces complete regression. In the similar situation angiopoietin-2 induces the destabilization of blood vessels, and the angiogenic factor VEGF produced by the tumor induces the massive formation of new vessels. When human melanoma cells A375 are stably transfected to produce the soluble variant of the angiopoietin receptor TIE-2 (sTIE-2), they show a substantial inhibition of tumor growth on nude mice. Similar effects have been seen with the soluble variant of the VEGF receptor FLT-1 (sFLT-1). In both cases, the vessel density of the tumors is significanty reduced. These experiments show that the inhibition of the angiopoietin/TIE-2 system, similar to the inhibition of the VEGF/VEGF receptor system, has an antitumoral effect, most probably due to the inhibition of tumor angiogenesis. Thus, inhibition of both signalling systems seem to be a valid strategy for the development of novel antiangiogenic therapies. Recently, the inhibition of the VEGF receptor tyrosine kinase by the compound PTK787/ZK222584 has been shown to substantially inhibit tumor growth and metastases formation. This compound has now entered clinical trials at the Tumor Biology Center in Freiburg i.Br. A preliminary evaluation of phase I study shows a very promising clinical outcome.